Therapeutic methods for muscular or neuromuscular disorders
The disclosure provides methods for treating neuromuscular disorders in mammals. The disclosed methods include administering therapeutically effective amounts of a GDF-8 inhibitor and a corticosteroid to a subject susceptible to, or having, a neuromuscular disorder, so as to maintain desirable levels of muscle function.
1. A method of treating a mammal with a decrease in muscle strength or muscle mass, comprising administering to the mammal a therapeutically effective amount of at least one Growth and Differentiation Factor-8 (GDF-8) inhibitor and a therapeutically effective amount of at least one corticosteroid in the amounts and for a period of time sufficient to treat a decrease in muscle strength or muscle mass.
2. The method of claim 1 , wherein the decrease in muscle strength or muscle mass is evaluated by at least one parameter chosen from muscle mass, muscle contraction force, serum creatine kinase (CK) concentration, or muscle morphology.
3. The method of claim 1 , wherein the muscle is chosen from at least one of gastrocnemius, tibialis anterior, quadriceps, extensor digitorum longus, cardiac muscle, or diaphragm muscle.
4. The method of claim 1 , wherein treating said mammal results in increased body weight of said mammal.
5. The method of claim 1 , wherein treating said mammal results in increased grip strength.
6. The method of claim 1 , wherein the mammal is human.
7. The method of claim 1 , wherein the corticosteroid is chosen from at least one of:
(a) at least one of beclomethasone dipropionate, budesonide, cortisol, dexamethasone, fluticason propionate, mometasone furoate, prednisone, or triamcinolone acetonide;
(b) a derivative of at least one of beclomethasone dipropionate, budesonide, cortisol, dexamethasone, fluticason propionate, mometasone furoate, prednisone, or triamcinolone acetonide; or
(c) a pharmaceutically acceptable salt of at least one of beclomethasone dipropionate, budesonide, cortisol, dexamethasone, fluticason propionate, mometasone furoate, prednisone, or triamcinolone acetoniden.
8. The method of claim 1 , wherein the corticosteroid is prednisone or prednisolone.
9. The method of claim 1 , wherein the corticosteroid is administered at a dose between 0.1 and 2.0 mg/kg/day.
10. The method of claim 1 , wherein the corticosteroid is administered orally.
11. The method of claim 1 , wherein the method results in treating of cardiomyopathy of said mammal.
12. The method of claim 1 , wherein the administration of GDF-8 inhibitor and corticosteroid is concurrent.
13. The method of claim 1 , wherein the administration of GDF-8 inhibitor and corticosteroid is consecutive.
14. The method of claim 1 , wherein the GDF-8 inhibitor is chosen from an antibody to GDF-8, an antibody to a GDF-8 receptor, a soluble GDF-8 receptor, a GDF-8 propeptide, follistatin, or a follistatin-domain-containing protein.
15. The method of claim 14 , wherein the antibody to GDF-8 is chosen from JA-16, Myo29, Myo28, or Myo22.
16. The method of claim 14 , wherein the GDF-8 propeptide is mutated at an aspartate residue.
17. The method of claim 14 , wherein the GDF-8 propeptide is joined to the Fc portion of an immunoglobulin.
18. The method of claim 14 , wherein the GDF-8 receptor is ActRIIB.
19. The method of claim 14 , wherein the GDF-8 receptor is joined to the Fc portion of an immunoglobulin.
20. The method of claim 14 , wherein the GDF-8 inhibitor is follistatin.
21. The method of claim 14 , wherein the follistatin-domain-containing protein is GASP-1.
22. A method of treating muscle weakness, comprising administering to a mammal a therapeutically effective amount of at least one GDF-8 inhibitor and a therapeutically effective amount of at least one corticosteroid in the amounts and for a period of time sufficient to treat loss of muscle strength.
23. The method of claim 22 , wherein the mammal is human.
24. The method of claim 22 , wherein the corticosteroid is chosen from at least one of:
(a) at least one of beclomethasone dipropionate, budesonide, cortisol, dexamethasone, fluticason propionate, mometasone furoate, prednisone, or triamcinolone acetonide;
(b) a derivative of at least one of beclomethasone dipropionate, budesonide, cortisol, dexamethasone, fluticason propionate, mometasone furoate, prednisone, or triamcinolone acetonide; or
(c) a pharmaceutically acceptable salt of at least one of beclomethasone dipropionate, budesonide, cortisol, dexamethasone, fluticason propionate, mometasone furoate, prednisone, or triamcinolone acetoniden.
25. The method of claim 22 , wherein the corticosteroid is prednisone or prednisolone.
26. The method of claim 22 , wherein the corticosteroid is administered at a dose between 0.1 and 2.0 mg/kg/day.
27. The method of claim 22 , wherein the corticosteroid is administered orally.
28. The method of claim 22 , wherein the GDF-8 inhibitor is chosen from an antibody to GDF-8, an antibody to a GDF-8 receptor, a soluble GDF-8 receptor, a GDF-8 propeptide, follistatin, or a follistatin-domain-containing protein.
29. The method of claim 28 , wherein the antibody to GDF-8 is chosen from JA-16, Myo29, Myo28, or Myo22.
30. The method of claim 28 , wherein the GDF-8 propeptide is mutated at an aspartate residue.
31. The method of claim 28 , wherein the GDF-8 propeptide is joined to the Fc portion of an immunoglobulin.
32. The method of claim 28 , wherein the GDF-8 receptor is ActRIIB.
33. The method of claim 28 , wherein the GDF-8 receptor is joined to the Fc portion of an immunoglobulin.
34. The method of claim 28 , wherein the GDF-8 inhibitor is follistatin.
35. The method of claim 28 , wherein the follistatin-domain-containing protein is GASP-1.
36. A method of treating corticosteroid-induced muscle atrophy in a mammal that is currently undergoing corticosteroid therapy, comprising administering to a mammal a therapeutically effective amount of at least one GDF-8 inhibitor.
37. The method of claim 36 , wherein the mammal is human.
38. The method of claim 36 , wherein the corticosteroid is chosen from at least one of:
(a) at least one of beclomethasone dipropionate, budesonide, cortisol, dexamethasone, fluticason propionate, mometasone furoate, prednisone, or triamcinolone acetonide;
(b) a derivative of at least one of beclomethasone dipropionate, budesonide, cortisol, dexamethasone, fluticason propionate, mometasone furoate, prednisone, or triamcinolone acetonide; or
(c) a pharmaceutically acceptable salt of at least one of beclomethasone dipropionate, budesonide, cortisol, dexamethasone, fluticason propionate, mometasone furoate, prednisone, or triamcinolone acetoniden.
39. The method of claim 36 , wherein the corticosteroid is prednisone or prednisolone.
40. The method of claim 36 , wherein the corticosteroid is administered at a dose between 0.1 and 2.0 mg/kg/day.
41. The method of claim 36 , wherein the corticosteroid is administered orally.
42. The method of claim 36 , wherein the GDF-8 inhibitor is chosen from an antibody to GDF-8, an antibody to a GDF-8 receptor, a soluble GDF-8 receptor, a GDF-8 propeptide, follistatin, or a follistatin-domain-containing protein.
43. The method of claim 42 , wherein the antibody to GDF-8 is chosen from JA-16, Myo29, Myo28, or Myo22.
44. The method of claim 42 , wherein the GDF-8 propeptide is mutated at an aspartate residue.
45. The method of claim 42 , wherein the GDF-8 propeptide is joined to the Fc portion of an immunoglobulin.
46. The method of claim 42 , wherein the GDF-8 receptor is ActRIIB.
47. The method of claim 42 , wherein the GDF-8 receptor is joined to the Fc portion of an immunoglobulin.
48. The method of claim 42 , wherein the GDF-8 inhibitor is follistatin.
49. The method of claim 42 , wherein the follistatin-domain-containing protein is GASP-1.
50. A method of treating a neuromuscular disorder, comprising administering to a mammal having the neuromuscular disorder a therapeutically effective amount of at least one GDF-8 inhibitor and a therapeutically effective amount of at least one corticosteroid in the amounts and for a period of time sufficient to treat the neuromuscular disorder.
51. The method of claim 50 , wherein the neuromuscular disorder is a muscular dystrophy.
52. The method of claim 51 , wherein the muscular dystrophy is Duchenne muscular dystrophy.
53. The method of claim 51 , wherein the muscular dystrophy is Becker muscular dystrophy.
54. The method of claim 50 , wherein the mammal is human.
55. The method of claim 50 , wherein the corticosteroid is chosen from at least one of:
(a) at least one of beclomethasone dipropionate, budesonide, cortisol, dexamethasone, fluticason propionate, mometasone furoate, prednisone, or triamcinolone acetonide;
(b) a derivative of at least one of beclomethasone dipropionate, budesonide, cortisol, dexamethasone, fluticason propionate, mometasone furoate, prednisone, or triamcinolone acetonide; or
(c) a pharmaceutically acceptable salt of at least one of beclomethasone dipropionate, budesonide, cortisol, dexamethasone, fluticason propionate, mometasone furoate, prednisone, or triamcinolone acetoniden.
56. The method of claim 50 , wherein the corticosteroid is prednisone or prednisolone.
57. The method of claim 50 , wherein the corticosteroid is administered at a dose between 0.1 and 2.0 mg/kg/day.
58. The method of claim 50 , wherein the corticosteroid is administered orally.
59. The method of claim 50 , wherein the GDF-8 inhibitor is chosen from an antibody to GDF-8, an antibody to a GDF-8 receptor, a soluble GDF-8 receptor, a GDF-8 propeptide, follistatin, or a follistatin-domain-containing protein.
60. The method of claim 59 , wherein the antibody to GDF-8 is chosen from JA-16, Myo29, Myo28, or Myo22.
61. The method of claim 59 , wherein the GDF-8 propeptide is mutated at an aspartate residue.
62. The method of claim 59 , wherein the GDF-8 propeptide is joined to the Fc portion of an immunoglobulin.
63. The method of claim 59 , wherein the GDF-8 receptor is ActRIIB.
64. The method of claim 59 , wherein the GDF-8 receptor is joined to the Fc portion of an immunoglobulin.
65. The method of claim 59 , wherein the GDF-8 inhibitor is follistatin.
66. The method of claim 59 , wherein the follistatin-domain-containing protein is GASP-1.
67. The method of claim 59 , wherein the method results in treating of cardiomyopathy of said mammal.
68. The method of claim 59 , wherein the administration of GDF-8 inhibitor and corticosteroid is concurrent.
69. The method of claim 59 , wherein the administration of GDF-8 inhibitor and corticosteroid is consecutive.